A Switch between One- and Two-electron Chemistry of the Human Flavoprotein Iodotyrosine Deiodinase Is Controlled by Substrate

Hu, Jimin; Chuenchor, W.; Rokita, Steven E.

doi:10.1074/jbc.m114.605964

Cited by 44 publications

(258 citation statements)

References 54 publications

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“…Defects in this enzyme can lead to iodide deficiency, which can have several detrimental effects to health such as hypothyroidism. The mechanism employed by iodotyrosine deiodinase has not still been fully established, although recent structures of the enzyme bound to its substrate have provided some insight [51,156]. The enzyme contains an FMN cofactor which plays a key role in the catalytic process by carrying out a stepwise reduction of the substrate by means of sequential one-electron transfers and not through a single two-electron transfer as previously proposed [51,157,158].…”

Section: Ec 1211: Reductive Dehalogenasesmentioning

confidence: 95%

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Vidal

Kelly

Mordaka

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

248

147

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A B S T R A C T NAD(P)H-dependent oxidoreductases catalyze the reduction or oxidation of a substrate coupled to the oxidation or reduction, respectively, of a nicotinamide adenine dinucleotide cofactor NAD(P)H or NAD(P) + . NAD(P)Hdependent oxidoreductases catalyze a large variety of reactions and play a pivotal role in many central metabolic pathways. Due to the high activity, regiospecificity and stereospecificity with which they catalyze redox reactions, they have been used as key components in a wide range of applications, including substrate utilization, the synthesis of chemicals, biodegradation and detoxification. There is great interest in tailoring NAD(P)H-dependent oxidoreductases to make them more suitable for particular applications. Here, we review the main properties and classes of NAD(P)H-dependent oxidoreductases, the types of reactions they catalyze, some of the main protein engineering techniques used to modify their properties and some interesting examples of their modification and application.

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Section: Ec 1211: Reductive Dehalogenasesmentioning

confidence: 95%

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Vidal

Kelly

Mordaka

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

248

147

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“…In the nitro-FMN reductase superfamily, flavin dependent dehalogenases can stabilize the flavin semiquinone following substrate binding [33]. A single mutation was recently shown to switch a dehalogenase to a nitro-reductase, by altering the N5 hydrogen pattern and thereby the inherent ability to promote one versus two-electron chemistry [34].…”

Section: Catalytic Cycles and New Chemistriesmentioning

confidence: 99%

Sweating the assets of flavin cofactors: new insight of chemical versatility from knowledge of structure and mechanism

Leys

Scrutton

2016

Current Opinion in Structural Biology

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Flavins are arguably one of the most versatile cofactors by virtue of the reactivity of the isoalloxazine ring system. A varied catalogue of reactions for the diverse family of flavoenzymes has been reported, leading to unifying concepts in (long-range) electron transfer, oxygen activation, photochemistry and substrate redox reactions. Recent examples of unprecedented flavin chemistry have been reported that uncover hidden depths of the flavoenzyme chemical repertoire. These include ring expansion of flavin through prenylation and formation of the superoxidized flavin-N5 oxide species. These and other new flavin based species are reviewed here and suggest further exciting discoveries await the flavoenzymology field.

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“…The NADPHdependence of IYD was lost upon solubilization, however, a finding that has been explained by loss of an unidentified intermediate electron carrier connecting NADPH and IYD (Rokita et al 2010). The exact mechanism of IYD is not established, but it is clear that it does not involve a catalytic thiol and relies instead on the presence of a protein-bound FMN (Hu et al 2015; Fig. 2A).…”

Section: Introductionmentioning

confidence: 99%

New insights into the structure and mechanism of iodothyronine deiodinases

Schweizer¹,

Steegborn²

2015

Journal of Molecular Endocrinology

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Iodothyronine deiodinases are a family of enzymes that remove specific iodine atoms from one of the two aromatic rings in thyroid hormones (THs). They thereby fine-tune local TH concentrations and cellular TH signaling. Deiodinases catalyze a remarkable biochemical reaction, i.e., the reductive elimination of a halogenide from an aromatic ring. In metazoans, deiodinases depend on the rare amino acid selenocysteine. The recent solution of the first experimental structure of a deiodinase catalytic domain allowed for a reappraisal of the many mechanistic and mutagenesis data that had been accumulated over more than 30 years. Hence, the structure generates new impetus for research directed at understanding catalytic mechanism, substrate specificity, and regulation of deiodinases. This review will focus on structural and mechanistic aspects of iodothyronine deiodinases and briefly compare these enzymes with dehalogenases, which catalyze related reactions. A general mechanism for the selenium-dependent deiodinase reaction will be described, which integrates the mouse deiodinase 3 crystal structure and biochemical studies. We will summarize further, sometimes isoform-specific molecular features of deiodinase catalysis and regulation, and we will then discuss available compounds for modulating deiodinase activity for therapeutic purposes.

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A Switch between One- and Two-electron Chemistry of the Human Flavoprotein Iodotyrosine Deiodinase Is Controlled by Substrate

Cited by 44 publications

References 54 publications

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Review of NAD(P)H-dependent oxidoreductases: Properties, engineering and application

Sweating the assets of flavin cofactors: new insight of chemical versatility from knowledge of structure and mechanism

New insights into the structure and mechanism of iodothyronine deiodinases

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